Project Summary/Abstract The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) at Columbia University and its subcontracted sites at the University of California, San Diego have played a major role over the past 16 years in furthering the understanding of nonalcoholic fatty liver disease in children and adults. Given that NAFLD is the most common chronic liver disease in the United States and that known outcomes include cirrhosis, liver transplant and liver cancer, it is imperative that we develop better noninvasive measures to diagnose with more severe or progressive forms of NAFLD and that we find improved therapies with unique and rational targets. The proposal in this limited competition renewal for our Clinical Center demonstrates the progress made in longitudinal database studies and significant findings in past and current/ongoing randomized clinical trials in adults and children. Our Center and the Network describe plans for completion and continued development of clinical trials, for finding novel bio-imaging methods to assess response to therapy, to define and evaluate the performance of imaging as a noninvasive marker that might be used as a surrogate for certain features of NAFLD/NASH and as a means of tracking disease progression and to complete and develop ancillary studies for understanding the role of genetic and environmental factors in modulating the course of disease. In this regard, we lead studies in developing proteomic reagents as predictive and diagnostic markers for NAFLD; in elucidating the role of the gut microbiome, the role of nuclear hormone receptors, and the role of genetic variants in pediatric NAFLD. We intend to continue to play leading roles in the NASH CRN, as the PI is Co-Chair of the Steering Committee and Database Committee, a member of the Executive Committee, and Chair of the Pediatric Committee. Our Centers? leading role in enrollment, along with our leadership in recruitment and retention of adults, children and minorities in the NASH CRN are expected to continue through completion of current trials and initiation of newly proposed studies.